L-AP4 sensitive glutamate receptors

Details L-AP4 sensitive glutamate receptors L-AP4 sensitive glutamate receptors

1993-12-30

2001-08-14

Ulm, John (Department: 1646)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S069100, C435S252300, C435S320100, C530S350000, C536S023500

Reexamination Certificate

active

06274330

ABSTRACT:

BACKGROUND OF THE INVENTION
Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. The neurotransmitter activity of glutamate is primarily mediated by ligand-gated ion channels. The observation that glutamate also induces responses mediated by second messengers has led to the discovery of a distinct group of glutamate receptors coupled to G proteins, termed metabotropic receptors (mGluRs). Schoepp and Conn,
Trends Pharmacol. Sci
. 14: 13-20 (1993). The first described action of the glutamate metabotropic receptors was inositol phospholipid (PI) hydrolysis. Nicoletti et al.,
J. Neurochem
. 46: 40-46 (1986) and Sugiyama et al.,
Nature
325: 531-533 (1987). Molecular cloning techniques have revealed a large family of metabotropic receptors with distinct transduction mechanisms, patterns of expression and sensitivities to glutamate agonists. Schoepp and Conn, supra.
Consistent with the molecular heterogeneity observed for the metabotropic receptors, electrophysiological studies have suggested diverse roles for these receptors in synaptic plasticity, presynaptic inhibition and regulation of cell excitability by ion channel modulation. Bashir et al.,
Nature
363: 347-363 (1993); Linden et al.,
Neuron
7: 81-89 (1991); Baskys and Malenka,
J. Physiol
. (
Lond
.) 444: 687-701 (1991); Charpak et al.
Nature
347: 765-767 (1990); and Lester and Jahr,
Neuron
5: 741-749 (1990). However, the specific mGluR receptors mediating these cellular functions are largely undefined.
Evidence for a physiological role for specific mGluR subtypes has been derived from work with selective agonists and antagonists of the receptors. For example, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) is a selective and potent activator of the mGluR1, mGluR2, mGluR3 and mGluR5 receptors. Masu et al.,
Nature
349: 760-765 (1991); Abe et al.,
J. Biol. Chem
. 267: 13361-13368 (1992); Tanabe et al., Neuron 8: 169-179 (1992); and Tanabe et al.,
J. Neurosci
. 13: 1372-1378 (1993). L-2-amino-4-phosphonobutryic acid (L-AP4) has been shown to activate mGluR4 and mGluR6. Id., Thomsen et al.,.
Eur. J. Pharmacol
. 227: 361-362 (1992); Nakajima et al.,
J. Biol. Chem
. 268: 11868-11873 (1993). L-AP4 inhibits transmitter release and voltage-dependent calcium entry in selected brain and spinal cord neurons. Koerner and Cotman,
Brain Res
. 216: 192-198 (1981); Trombley and Westbrook,
J. Neurosci
. 12: 2-43-2050 (1992); and Sahara and Westbrook,
J. Neurosci
. 13: 3041-3050 (1993). But in retinal bipolar neurons, postsynaptic L-AP4 receptors activate a phosphodiesterase. Nawy and Jahr,
Nature
346: 269-271 (1990).
Multiple mGluR subtypes can be present within the same group of neurons. As the cellular and subcellular localization of specific mGluRs may be important in shaping incoming sensory information, it is important to identify other receptors of the mGluR group. Once identified, specific agonists and antagonists can be prepared to modulate the responses associated with the receptor. Quite surprisingly, the present invention identifies a L-AP4 sensitive receptor that modulates transmitter release in neurons that express neither mGluR4 nor mGluR6, and fulfills other related needs.
SUMMARY OF THE INVENTION
The present invention provides novel isolated and purified metabotropic mGluR proteins referred to as mGluR7. The proteins may bind glutamate and induce cytoplasmic signal transduction. Allelic variants and mutations of mGluR7 proteins are included.
Also provided are isolated polynucleotides encoding mGluR7 and probes to the polynucleotides. The polynucleotides may be present in expression cassettes of the present invention that are useful for cellular transformation. Such transformed cell lines are also provided by the present invention. Transformed cells may be employed in methods for identifying compounds that alter mGluR7 metabolism.
Antibodies to mGluR7 receptor proteins are also provided by the present invention. The antibodies may be polyclonal or monoclonal. The antibodies may be employed to detect the presence of mGluR7 in biological samples, such as tissue homogenates, biological fluids, or cell surfaces.


REFERENCES:
patent: 5089386 (1992-02-01), Stackebrandt et al.
patent: 5202257 (1993-04-01), Heinemann et al.
patent: 0 569 240 A1 (1993-11-01), None
patent: 569240 (1993-11-01), None
patent: 0 600 278 A2 (1994-06-01), None
patent: 92/10583 (1992-06-01), None
patent: 95/08627 (1995-03-01), None
George et al. Macromolecular Sequencing and Synthesis, Alan R. Liss, Inc. pp. 127-149, 1988.*
Koerner and Cotman, “Micromolar L-2-amino-4-phosphonobutyric Acid Selectively Inhibits Perforant Path Synapses from Lateral Entorhinal Cortex”,Brain Res.216:192-198 (1981).
Houamad et al., “Expression of Functional GABA, Glycine and Glutamate Receptors in Xenopus Oocytes Infected with Rat Brain mRNA”,Nature310: 318-321, (Jul., 1984).
Nicoletti et al., “Coupling of Inositol Phospholipid Metabolism with Excitatory Amino Acid Recognition Sites in Rat Hippocampus”,J. Neurochem. 46: 40-46 (1986).
Sugiyama et al., “A New Type of glutamate Receptor Linked to Inositol Phospholipid Metabolism”,Nature325: 531-533 (Feb., 1987).
Hirono et al., “Characterization of Glutamate Receptors Induced in Xenopus Oocytes After Injection of Rat Brain mRNA”,Neurosci. Res. 6: 106-114, (1988).
Snutch, “The Use of Xenopus Oocytes to Probe Synaptic Communication”,Trends In Neurosci11(6): 250-256, (1988).
Fong et al., “Properties of Two Classes of Rat Brain Acidic Amino Acid Receptors Induced by Distinct mRNA Populations in Xenopus Oocytes”,Synapse2: 657-665, (1988).
Recasens et al., “A New Quisqualate Receptor Subtype (sAA2) Responsible for the Glutamate-induced Inositol Phosphate Formation in Rat Brain Synaptoneurosomes”,Neurochem. Int.13: 463-467 (1988).
Sugiyama et al., “Glutamate Receptor Subtypes May be Classified into Two Major Categories: A Study on Xenopus Oocytes Injected with Rat Brain mRNA”,Neuron3: 129-132, (Jul., 1989).
Hollmann et al., “Cloning by Functional Expression of a Member of the Glutamate Receptor Family”,Nature342: 643-648, (Dec., 1989).
Nawy and Jahr, “Suppression by Glutamate of cGMP-activated Conductance in Retinal Bipolar Cells”,Nature346: 269-271 (Jul., 1990).
Sommer et al., “Flip and Flop: A Cell-Specific Functional Switch in Glutamate-Operated Channels of the CNS”,Science249: 1580-1585, (Sep., 1990).
Charpak et al., “Potassium Conductances in Hippocampal Neurons Blocked by Excitatory Amino-acid Transmitters”,Nature347: 765-767 (Oct., 1990).
Schoepp et al., “Pharmacological and Functional Characteristics of Metabotropic Excitatory Amino Acid Receptors”,Trends Pharm. Sci., 11:508-515 (Dec., 1990).
Lester and Jahr, “Quisqualate Receptor-Mediated Depression of Calcium Currents in Hippocampal Neurons”,Neuron4: 741-749 (May, 1990).
Masu et al., “Sequence and Expression of a Metabotropic Glutamate Receptor”,Nature349: 760-765 (Feb., 1991).
Houamed et al., “Cloning, Expression, and Gene Structure of a G Protein-Coupled Glutamate Receptor from Rat Brain”,Science252: 1318-1321 (May, 1991).
Baskys and Malenka, “Agonists at Metabotropic Glutamate Receptors Presynaptically Inhibit EPSCs in Neonatal Rat Hippocampus”,J. Physiol.(Lond.) 444: 687-701 (1991).
Linden et al., “A Long-Term Depression of AMPA Currents in Cultured Cerebellar Purkinje Neurons”,Neuron7: 81-89 (Jul., 1991).
Abe et al., “Molecular Characterization of a Novel Metabotropic Glutamate Receptor mGluR5 Coupled to Inositol Phosphate/Ca2+Signal Transduction”,J. Biol. Chem.267: 13361-13368 (Jul., 1992).
Tanabe et al., “A Family of Metabotropic Glutamate Receptors”,Neuron8: 169-179 (Jan., 1992).
Trombley and Westbrook, “L-AP4 Inhibits Calcium Currents and Synaptic Transmission via a G-Protein-coupled Glutamate Receptor”,J. Neurosci. 12: 2043-2050 (Jun., 1992).
Thomsen et al., “L-2-Amino-4-phosphonobutyrate (L-AP4) is an Agonist at the Type IV Metabotropic Glutamate Receptor Which is Negatively Coupled to Adenylate Cyclase”,Eur. J. Pharmacol. 227: 361-362 (1992).
Bashir et al., “Induction of LTP in the Hippocampus Needs

Affiliated with

Also associated with

Rating

L-AP4 sensitive glutamate receptors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with L-AP4 sensitive glutamate receptors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and L-AP4 sensitive glutamate receptors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2518433